Tuberculosis (TB) disease is driven by a pathological inflammatory response that causes both acute symptoms and permanent lung damage. Anti-inflammatory therapies ameliorate these pathologies in animal models, and similar host-directed therapies (HDT) have the potential to improve patient outcomes. However, a number of issues make the use of immunomodulators in TB a complex endeavor. Most fundamentally, the local response to Mycobacterium tuberculosis (Mtb) is remarkably variable even within a single host, and any immunomodulator has the potential to exacerbate some lesions while improving others. This situation is made more complex by the requirement that HDT be used in conjunction with antimicrobial chemotherapy, as antibiotic efficacy can also be influenced by host immunity in unexpected ways. Finally, since comorbidities such as HIV infection are common in the populations where these therapies could have the highest impact, TB-directed HDT should not exacerbate another infection. Given these realities, we will optimize a novel TB regimen by specifically pairing host- and pathogen-directed agents that accentuate the overall efficacy of treatment, and use preclinical models that mimic the variable disease observed in humans. Our specific strategy is based on the observations that the inflammasome/interleukin 1 (IL-1) axis both exacerbates TB disease and limits the effectiveness of the oxazolidinone class of antibiotics, drugs that are not compromised by preexisting resistance. Based on these data, we hypothesize that IL-1 and/or inflammasome antagonists can be used to simultaneously reduce Mtb-induced lung damage, accelerate bacterial clearance, and improve the tolerability of this important new antibiotic class. We will use small animal models to optimize this combination host- and bacteria-directed regimen. After rigorous pharmacokinetic optimization, this combination regimen will be tested in macaques, the preclinical model that most closely mimics human disease. Our ability to monitor treatment success at each independent lesion by quantitative PET/CT imaging will be essential to understanding the effects of immunomodulation in this highly variable disease. Finally, the optimized and validated combination regimen will be tested in a proof-of-concept clinical trial that will assess the efficacy of therapy using a variet of metrics including the quantitative PET/CT-based evaluation that was validated in macaques. This program represents a fundamentally new approach to TB therapy based on the specific pairing of host- and pathogen-targeted agents.